Previous work in this laboratory has shown that, in freely moving rats, the pattern of neuronal transmission from the entorhinal cortex through the hippocampal formation to limbic system target structures depends on the particular waking or sleeping of the experimental animal. We have been engaged in an investigation of possible brainstem substrates for this behavioral modulation of hippocampal activity. Three such sources have been identified. Our findings indicate a specific role for the noradrenergic input to the dentate gyrus as well as an effect of the serotonergic input. A third source is a non-aminergic, fast-conducting pathway which arises in the medullary reticular formation, courses through or synapses in the raphe nuclei and has a final synapse in the caudal supramammilary region of the midbrain before terminating in the dentate gyrus. We propose a series of experiments to further delineate the effects of these inputs on hippocampal activity. The studies include the stimulation of brainstem afferents and subsequent recording of the effects on neuronal transmission through the dentate gyrus in both freely moving and anesthetized animals, unit driving and recording, and the central injection of norepinephrine, serotonin and related drugs. To elucidate the role of the fast-conducting pathway arising in the reticular formation, we also propose to record, in freely moving animals, the unit activity of neurons in the supramammillary region identified as part of this pathway. The function served by the selective changes in the paths of information flow through the hippocampus with waking and sleeping behaviors is unknown, but it presumably reflects a basic limbic system process. To investigate the question of function, we propose to study unit activity of hippocampal formation neurons while rats are both awake and asleep. The firing characteristics of neurons which exhibit enhanced firing associated with spatial location during the waking state (place units) will be observed throughout subsequent waking-sleeping cycles and compared to the characteristics of neurons, recorded simultaneously, which have not shown enhanced firing during the waking state.